Multiple sclerosis (MS) is an autoimmune disease currently affecting two million people around the world, mainly in well developed countries, with an important inflammatory component.
Six medicaments are currently approved for the treatment of relapsing forms of MS, including: three interferon-β preparations [Avonex (interferon beta-1a) (Biogen Idec, Cambridge, Mass., United States), Betaseron®/Betaferon® (interferon beta-1b) (Berlex, Montville, N.J., United States), and Rebif® (Serono, Geneva, Switzerland)]; glatiramer acetate (GA) (Copaxone®; Teva, Nordani, Israel); mitoxantrone (Novantrone®; Serono, Geneva, Switzerland); and natalizumab (Tysabri®; Biogen Idec) [Jacobs et al. Ann Neurol (1996), 39:285-294; IFNβ Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology (1993), 43:655-661; PRISMS (Prevention of Relapses and Disability by Interferon beta 1a Subcutaneously in Multiple Sclerosis) Study Group. Lancet (1998), 352:1498-1504. Johnson et al. Neurology (1995); 45:1268-1276. Hartung et al. Lancet (2002), 360:2018-2025 Polman et al. N Engl J Med (2006), 354:899-910]. Interferons-β and glatiramer acetate act as first-line agents, and have been routinely used for approximately a decade. The drawback of these approved anti-MS drugs is that they need to be administered subcutaneously (Interferon-beta or GA), intramuscularly (interferon beta-1a) or intravenously (Natalizumab).
The pathophysiology of MS is multifaceted and it may be necessary to combine different drugs with complementary mechanisms of action to obtain maximal clinical benefit in patients who do not respond to conventional monotherapies. The main clinical rationale for using drug combinations is obtaining additive or even synergistic therapeutic effects [Reid. J Hum Hypertens (1995), 9 (Suppl 4):S19-S23]. There are two pharmacological bases for using a combination of two or more drugs: Class 1 combination therapies include two (or more) drugs that are considered independent from one other and target different aspects of the harmful mechanisms underlying the disease [Toews et al. Proc Am Thorac Soc 2005; 2:282-289]. In the case of MS, for example, one drug may target cell traffic in the CNS, whereas another drug may affect cell activation. Class 2 drug combinations include two or more pharmacological agents that have different molecular targets within a single cell type, or a single response mechanism in that cell type [Toews et al. (2005) mentioned above].
Glatiramer acetate, also known as Copolymer 1, Cop 1, copaxone, or GA, is a non-pathogenic synthetic random copolymer made up of the four amino acids: L-Glu, L Lys, L-Ala, and L-Tyr. It has been described that, due to its different mechanisms of action, glatiramer acetate may represent the ideal candidate to accompany other agents to achieve complementary and potentially synergistic therapeutic effects (Costello et al. Curr Op Neurology (2007), 20:281-285). Boggild [Boggild. J Neurol (2006), 253 (Suppl 6):VI/45-VI/51] and Ramtahal et al. [Ramtahal et al. J Neurol (2006); 253:1160-1164] used mitoxantrone as an induction therapy followed by maintenance therapy with GA in a series of non-random, uncontrolled observational cases, and observed a 90% reduction in the relapse rate among patients. WO2005009333 describes that Copolymer 1 (GA)-related heteropolymers or peptides in combination with other immunosuppressive drugs induce an unexpected synergistic effect, and thus improve the efficacy of the current immunosuppressive regimens.
Unfortunately, therapy with GA has some drawbacks deriving from its required fixed dose and the fact that the response is highly sensitive to the specific regimen of administration, requiring daily doses in order to achieve its efficacy. Furthermore, due to its vaccine design, the individual immune responses after GA immunization differ between individuals depending on the genetic background or other immunological factors, leading to a range of different degrees of responders. In fact, the current efficacy of GA in preventing new relapses in MS is not more than 25%. This limited efficacy prevents its widespread use in several countries and it is often prescribed for patients with a mild disease; patients with a more severe disease are frequently not treated with GA. As such, GA is nowadays only approved for the treatment of relapsing-remitting MS.
5′-methylthioadenosine (MTA) is a lipophilic sulfur-containing adenine nucleoside produced from S-adenosylmethionine (SAM) during the synthesis of the polyamines spermine and spermidine. MTA is capable of preventing acute Experimental Autoimmune Encephalomyelitis (EAE) and ameliorates Chronic-Relapsing EAE (RR-EAE), two different models of Multiple Sclerosis (MS), by means of the modulation of T cell activation, the decrease of inflammation and demyelination in the central nervous system [Moreno et al. Ann. Neurol. (2006) September, 60(3):323-334]. MTA has shown a dose-response effect with a wide range of doses without side effects. Furthermore, MTA is a suitable drug for oral formulations due to its small size and hydrophilic character. EP352609 describes the use of adenosine derivatives, particularly MTA, in preparing pharmaceutical compositions possessing immunostimulant activity. WO2006097547 describes the use of MTA in the prevention and/or treatment of autoimmune diseases, such as MS, and in the prevention and/or treatment of transplant rejection.
The mechanisms of action through which MTA exerts its immunomodulatory activity are complex [Williams-Ashman et al., Biochem Pharmacol. (1982), 31:277-288]. Nevertheless, it can be asserted that MTA specifically modulates the immune responses dependent on CD4+ cell activation through the chemical modulation of the signaling pathways.
GA has shown a competitive activity for the binding of the T-cell receptor specific for the Myelin Basic Protein (MBP). GA can be considered as a vaccine for inducing immune tolerance against brain self-antigens. It has been observed that therapy with GA induces a shift towards Th2 responses and the activation of regulatory T-cells that suppress the autoimmune response. Due to its vaccine-type mechanism of action, in order to be effective GA needs to induce an immune response against GA mediated by CD4+. Since MTA suppresses CD4+ activation, which is necessary for the generation of GA-specific T cell responses, it could be expected that the combination of MTA and GA could be neutral or even harmful.